The BlyS Ligand/Receptor Family
Three receptors, TACI (transmembrane activator or Calcium-Modulating Cyclophylin Ligand-interactor), BCMA (B-cell maturation antigen) and BAFF-R (receptor for B-cell activating factor, belonging to the TNF family), have been identified that have unique binding affinities for the two growth factors BlyS (B-lymphocyte stimulator) and APRIL (a proliferation-inducing ligand) (Marsters et al. Curr Biol 2000; 10(13): 785-788; Thompson et al. Science 2001; 293:21 08-2111). TACI and BCMA bind both BLyS and APRIL, while BAFF-R appears capable of binding only BLyS with high affinity (Marsters et al. Curr Biol 2000; 10(13):785-788; Thompson et al. Science 2001; 293:21 08-2111.). As a result, BLyS is able to signal through all three receptors, while APRIL only appears capable of signaling through TACI and BCMA. In addition, circulating heterotrimer complexes of BLyS and APRIL (groupings of three proteins, containing one or two copies each of BLyS and APRIL) have been identified in serum samples taken from patients with systemic immune-based rheumatic diseases, and have been shown to induce B-cell proliferation in vitro (Roschke et al. J Immunol 2002; 169: 4314-4321). Amongst the Ig-fusion proteins for all three receptors, only TACI-Fc5 was able to block the biological activity of the heterotrimeric complexes (Roschke et al. J Immunol 2002; 169: 4314-4321).
BLyS and APRIL are potent stimulators of B-cell maturation, proliferation and survival (Gross et al. Nature 2000; 404: 995-999. Gross et al. Immunity 2001; 15(2): 289-302. Groom et al. J Clin Invest 2002; 109(1): 59-68). BLyS and APRIL may be necessary for persistence of autoimmune diseases, especially those involving B-cells. Transgenic mice engineered to express high levels of BLyS exhibit immune cell disorders and display symptoms similar to those seen in patients with Systemic Lupus Erythematosus (Cheson et al. Revised guidelines for diagnosis and treatment. Blood 1996; 87:4990-4997. Cheema et al. Arthritis Rheum 2001; 44(6):1313-1319). Similarly, increased levels of BLyS/APRIL have been measured in serum samples taken from SLE patients and other patients with various autoimmune diseases like Rheumatoid Arthritis (Roschke et al. J Immunol 2002; 169:4314-4321; Mariette X., Ann Rheum Dis 2003; 62(2):168-171; Hahne et al. J Exp Med 1998; 188(6):1185-1190), extending the association of BLyS and/or APRIL and B-cell mediated diseases from animal models to humans.
Rheumatoid Arthritis
Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by non-specific, usually symmetric inflammation of the peripheral joints, potentially resulting in progressive destruction of articular and periarticular structures. About 1% of the population is affected, women two to three times more often than men. Although the precise etiology of the disease is elusive, strong evidence suggests RA is an autoimmune disease. Several auto-antibodies are associated with RA including rheumatoid factor (RF) which is frequently associated with more severe disease, anti-nuclear factors and antibodies against native collagen type II and citrullinated peptides.
Prominent immunologic abnormalities that may be important in the pathogenesis of RA include immune complexes found in joint fluid cells and in vasculitis. Contributing to these complexes are antibodies (such as RF) produced by plasma cells and T helper cells that infiltrate the synovial tissue and which can produce pro-inflammatory cytokines. Macrophages and their cytokines (e.g. TNF, GMCS-F) are also abundant in diseased synovium. Increased levels of adhesion molecules contribute to inflammatory cell emigration and retention in the synovial tissue. Increased macrophage-derived lining cells are also prominent, along with some lymphocytes.
The role of T cells in the pathogenesis of RA is well established, while that of B cells is less well known. Nevertheless, B cells play many potential roles in the pathogenesis of RA, including acting as antigen-presenting cells, secreting pro-inflammatory cytokines, producing rheumatoid factor auto-antibody and activating T cells. The potential role of B cells is further supported by the positive results of clinical trials testing rituximab, a monoclonal antibody directed against CD20, in RA patients, most notably when given in combination with methotrexate or cyclophosphamide. These findings suggest that B cells are an appropriate target for therapeutic intervention in RA.
Established treatments of RA include disease modifying anti-rheumatic drugs (DMARD) such as hydroxychloroquine, sulfasalazine, methotrexate, leflunomide, rituximab, infliximab, azathioprine, D-penicillamine, Gold (oral or intramuscular), minocycline and cyclosporine, coritcosteroids such as prednisone and non-steroidal anti-inflammatory drugs (NSAIDS). These treatments are generally nonspecific, are frequently associated with serious side-effects and do not significantly affect the progression of joint destruction. Consequently, there is a long-felt need in the art to develop new methods for treating RA.